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Adverse Drug Reactions and Gender Differences

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 40506

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Special Issue Editors

Dr. Concetta Rafaniello

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Guest Editor

Department of Experimental Medicine, University of Campania “L. Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy
Interests: pharmacovigilance; pharmacoepidemiology; prescriptive appropriateness and clinical research both pre- and postmarketing

Dr. Annalisa Capuano

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Guest Editor

Department of Experimental Medicine, University of Campania “L. Vanvitelli”, Via Santa Maria di Costantinopoli 16, 80138 Naples, Italy
Interests: pharmacovigilance; adverse drug reactions; pharmacists

Special Issue Information

Dear Colleagues,

In the era of personalized and precision medicine, gender differences continue to be a “grey zone” that requires better definition, especially in terms of drug response and tolerability. Many studies have attempt to associate gender difference with a specific drug response or drug toxicity, but more evidence is needed to bridge the gap. In terms of the drug safety profile, several studies suggest that women are more exposed to the risk of adverse drug reaction (ADR) occurrence than men; this difference could be due to a combination of sex differences, such as weight, height, body surface area, fat mass, plasma volume, total amount of body water, biological differences, and hormonal changes, and gender differences, including psychological, behavioral, and/or cultural differences. Therefore, gender and sex differences could result in different drug tolerability in terms of ADR frequency and seriousness. In this context, advances in pharmacology are essential to understand the gender differences associated with pharmacological treatments, with the aim of better defining the mechanisms underlying the differences in responses to drugs that, in turn, influence their tolerability. Considering that all women are still phased out from clinical trials, evidence from real world data is an important tool for identifying the true safety profiles of medicinal products in populations that have not been adequately studied, in order to promote gender-oriented and appropriate drug prescription. Although the data available regarding the impact of gender on the safety profiles of medicinal products shows a prevalence of ADR occurrence amongst females over males, gender-specific pharmacovigilance activities must be undertaken in order to reduce the risks associated with the use of medicinal products and to conduct a risk/benefit assessment in greater detail to elucidate the differences between men and women in terms of pharmacokinetics and pharmacodynamics.

In this Special Issue, experts are invited to submit clinical trial, experimental, original, and review articles that contribute to improving the understanding of the different drug safety profiles related to gender differences.

Dr. Concetta Rafaniello
Prof. Annalisa Capuano
Guest Editors

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Keywords

gender differences
adverse drug reaction
real world data
randomized clinical trial

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Published Papers (9 papers)

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Research

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18 pages, 1855 KiB

Open AccessArticle

Analysis of Factors Associated with Hiccups Using the FAERS Database

by Ryuichiro Hosoya, Reiko Ishii-Nozawa, Kota Kurosaki and Yoshihiro Uesawa

Pharmaceuticals 2022, 15(1), 27; https://doi.org/10.3390/ph15010027 - 24 Dec 2021

Cited by 8 | Viewed by 5445

Abstract

In this study, we used the large number of cases in the FDA adverse-event reporting system (FAERS) database to investigate risk factors for drug-induced hiccups and to explore the relationship between hiccups and gender. From 11,810,863 adverse drug reactions reported between the first quarter of 2004 and the first quarter of 2020, we extracted only those in which side effects occurred between the beginning and end of drug administration. Our sample included 1454 adverse reactions for hiccups, with 1159 involving males and 257 involving females (the gender in 38 reports was unknown). We performed univariate analyses of the presence or absence of hiccups for each drug and performed multivariate analysis by adding patient information. The multivariate analysis showed nicotine products to be key suspect drugs for both men and women. For males, the risk factors for hiccups included older age, lower body weight, nicotine, and 14 other drugs. For females, only nicotine and three other drugs were extracted as independent risk factors. Using FAERS, we were thus able to extract new suspect drugs for drug-induced hiccups. Furthermore, this is the first report of a gender-specific analysis of risk factors for hiccups that provides novel insights into drug-induced hiccups, and it suggests that the mechanism responsible is strongly related to gender. Thus, this study can contribute to elucidating the mechanism underlying this phenomenon. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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12 pages, 7576 KiB

Open AccessArticle

Incident Type 2 Diabetes Risk of Selective Estrogen Receptor Modulators in Female Patients with Breast Cancer

by Yeo-Jin Choi, Keunhyeong Bak, Yoon Yeo, Yongwon Choi and Sooyoung Shin

Pharmaceuticals 2021, 14(9), 925; https://doi.org/10.3390/ph14090925 - 14 Sep 2021

Cited by 8 | Viewed by 2858

Abstract

Accumulating evidence indicates a link between diabetes and cancer. Selective estrogen receptor modulators (SERMs) may increase diabetes risk via antiestrogen effects. This study investigated incident diabetes risk of SERM treatment and its effects on metastatic cancer and death prevention in breast cancer survivors. This retrospective cohort study included female patients with early-stage breast cancer, treated with or without SERMs, between 2008 and 2020 in a tertiary care hospital in Korea. Four propensity score-matched comparison pairs were designed: SERM use versus non-use, long-term use (≥1500 days) versus non-use, tamoxifen use versus non-use, and toremifene use versus non-use; then, logistic regression analysis was performed for risk analysis. SERMs in general were not associated with an elevated risk of diabetes; however, when used for ≥1500 days, SERMs—especially toremifene—substantially increased diabetes risk in breast cancer patients (OR 1.63, p = 0.048). Meanwhile, long-term SERM treatment was effective at preventing metastatic cancer (OR 0.20, p < 0.001) and death (OR 0.13, p < 0.001). SERM treatment, albeit generally safe and effective, may increase diabetes risk with its long-term use in women with breast cancer. Further studies are required to verify the association between toremifene treatment and incident diabetes. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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14 pages, 635 KiB

Open AccessArticle

Comparative Safety Profiles of Sedatives Commonly Used in Clinical Practice: A 10-Year Nationwide Pharmacovigilance Study in Korea

by Yeo-Jin Choi, Seung-Won Yang, Won-Gun Kwack, Jun-Kyu Lee, Tae-Hee Lee, Jae-Yong Jang and Eun-Kyoung Chung

Pharmaceuticals 2021, 14(8), 783; https://doi.org/10.3390/ph14080783 - 9 Aug 2021

Cited by 7 | Viewed by 4038

Abstract

This study aims to compare the prevalence and seriousness of adverse events (AEs) among sedatives used in critically ill patients or patients undergoing invasive procedures and to identify factors associated with serious AEs. Retrospective cross-sectional analysis of sedative-related AEs voluntarily reported to the Korea Adverse Event Reporting System from 2008 to 2017 was performed. All AEs were grouped using preferred terms and System Organ Classes per the World Health Organization—Adverse Reaction Terminology. Logistic regression was performed to identify factors associated with serious events. Among 95,188 AEs, including 3132 (3.3%) serious events, the most common etiologic sedative was fentanyl (58.8%), followed by pethidine (25.9%). Gastrointestinal disorders (54.2%) were the most frequent AEs. The most common serious AE was heart rate/rhythm disorders (33.1%). Serious AEs were significantly associated with male sex; pediatrics; etiologic sedative with etomidate at the highest risk, followed by dexmedetomidine, ketamine, and propofol; polypharmacy; combined sedative use; and concurrent use of corticosteroids, aspirin, neuromuscular blockers, and antihistamines (reporting odds ratio > 1, p < 0.001 for all). Sedative-induced AEs are most frequently reported with fentanyl, primarily manifesting as gastrointestinal disorders. Etomidate is associated with the highest risk of serious AEs, with the most common serious events being heart rate/rhythm disorders. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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18 pages, 320 KiB

Open AccessArticle

Risk of Hospitalization for Adverse Drug Events in Women and Men: A Post Hoc Analysis of an Active Pharmacovigilance Study in Italian Emergency Departments

by Giada Crescioli, Ennio Boscia, Alessandra Bettiol, Silvia Pagani, Giulia Spada, Giuditta Violetta Vighi, Roberto Bonaiuti, Mauro Venegoni, Giuseppe Danilo Vighi, Alfredo Vannacci, Niccolò Lombardi and on behalf of the MEREAFaPS Study Group

Pharmaceuticals 2021, 14(7), 678; https://doi.org/10.3390/ph14070678 - 15 Jul 2021

Cited by 10 | Viewed by 2765

Abstract

This post hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visits and hospitalization in women and men. During the study period (January 2007–December 2018), 61,855 reports of ADEs leading to ED visits were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13–176), antidepressants (ROR 1.12, CI 1.03–1.23) and antidiabetics (ROR 1.13, CI 1.02–1.24). Among men, only vitamin K antagonists (ROR 1.28, CI 1.09–1.50), opioids (ROR 1.30, CI 1.06–1.60) and digitalis glycosides (ROR 1.32, CI 1.09–1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidities were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing an adverse event following immunization (ROR 0.36, CI 0.27–0.48 and 0.83, 0.42–0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

13 pages, 465 KiB

Open AccessArticle

Cardiac Events Potentially Associated to Remdesivir: An Analysis from the European Spontaneous Adverse Event Reporting System

by Concetta Rafaniello, Carmen Ferrajolo, Maria Giuseppa Sullo, Mario Gaio, Alessia Zinzi, Cristina Scavone, Francesca Gargano, Enrico Coscioni, Francesco Rossi and Annalisa Capuano

Pharmaceuticals 2021, 14(7), 611; https://doi.org/10.3390/ph14070611 - 25 Jun 2021

Cited by 33 | Viewed by 5931

Abstract

Remdesivir was recommended for hospitalized patients with COVID-19. As already reported in the Summary of Product Characteristics, most of remdesivir’s safety concerns are hepatoxicity and nephrotoxicity related. However, some cases have raised concerns regarding the potential cardiac events associated with remdesivir; therefore, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency requested to investigate all available data. Therefore, we analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on cardiac adverse events. From April to December 2020, 1375 ICSRs related to remdesivir were retrieved from EudraVigilance, of which 863 (62.8%) were related to male and (43.3%) adult patients. A total of 82.2% of all AEs (N = 2604) was serious and one third of the total ICSRs (N = 416, 30.3%) had a fatal outcome. The most frequently reported events referred to hepatic/hepatobiliary disorders (19.4%,), renal and urinary disorders (11.1%) and cardiac events (8.4%). Among 221 cardiac ICSRs, 69 reported fatal outcomes. Other drugs for cardiovascular disorders were reported as suspected/concomitant together with remdesivir in 166 ICSRs (75.1%), 62 of which were fatal. Moreover, the mean time to overall cardiac event was 3.3 days (±2.2). Finally, disproportionality analysis showed a two-fold increased risk of reporting a cardiac adverse event associated with remdesivir compared to both hydroxychloroquine and azithromycin. This study showed that remdesivir could be associated to risk of cardiac events, suggesting a potential safety signal which has not been completely evaluated yet. Further studies are needed to confirm these findings. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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8 pages, 236 KiB

Open AccessArticle

Signal Detection of Adverse Drug Reactions of Cephalosporins Using Data from a National Pharmacovigilance Database

by Jung-Yoon Choi, Jae-Hee Choi, Myeong-Gyu Kim and Sandy-Jeong Rhie

Pharmaceuticals 2021, 14(5), 425; https://doi.org/10.3390/ph14050425 - 2 May 2021

Cited by 6 | Viewed by 3318

Abstract

This case-non-case study aims to detect signals not currently listed on cephalosporin drug labels. From 2009 to 2018, adverse event (AE) reports concerning antibacterial drugs (anatomical therapeutic chemical (ATC) code J01) in the Korea Adverse Events Reporting System (KAERS) database were examined. For signal detection, three indices of disproportionality, proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC), were calculated. The list of signals was compared with ADRs on the drug labels from the United States, United Kingdom, Japan, and South Korea. A total of 163,800 cephalosporin–AE combinations and 72,265 all other J01–AE combinations were analyzed. This study detected 472 signals and 114 new signals that are not included on the drug labels. Cefatrizine–corneal edema (PRR, 440.64; ROR, 481.67; IC, 3.84) and cefatrizine–corneal ulceration (PRR, 346.22; ROR, 399.70; IC, 4.40) had the highest PRR, ROR, and IC among all signals. Additionally, six serious AEs that were not listed on drug labels such as cefaclor-induced stupor (ten cases) and cefaclor-induced respiratory depression (four cases) were found. Detecting signals using a national pharmacovigilance database is useful for identifying unknown ADRs. This study identified signals of cephalosporins that warrant further investigation. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

Review

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19 pages, 509 KiB

Open AccessReview

A Sex- and Gender-Based Analysis of Adverse Drug Reactions: A Scoping Review of Pharmacovigilance Databases

by Andreea C. Brabete, Lorraine Greaves, Mira Maximos, Ella Huber, Alice Li and Mê-Linh Lê

Pharmaceuticals 2022, 15(3), 298; https://doi.org/10.3390/ph15030298 - 28 Feb 2022

Cited by 39 | Viewed by 8128

Abstract

Drug-related adverse events or adverse drug reactions (ADRs) are currently partially or substantially under-reported. ADR reporting systems need to expand their focus to include sex- and gender-related factors in order to understand, prevent, or reduce the occurrence of ADRs in all people, particularly women. This scoping review describes adverse drug reactions reported to international pharmacovigilance databases. It identifies the drug classes most commonly associated with ADRs and synthesizes the evidence on ADRs utilizing a sex- and gender-based analysis plus (SGBA+) to assess the differential outcomes reported in the individual studies. We developed a systematic search strategy and applied it to six electronic databases, ultimately including 35 papers. Overall, the evidence shows that women are involved in more ADR reports than men across different countries, although in some cases, men experience more serious ADRs. Most studies were conducted in higher-income countries; the terms adverse drug reactions and adverse drug events are used interchangeably, and there is a lack of standardization between systems. Additional research is needed to identify the relationships between sex- and gender-related factors in the occurrence and reporting of ADRs to adequately detect and prevent ADRs, as well as to tailor and prepare effective reporting for the lifecycle management of drugs. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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14 pages, 665 KiB

Open AccessReview

Gender and Sex-Related Differences in Normal Tissue Effects Induced by Platinum Compounds

by Loredana G. Marcu

Pharmaceuticals 2022, 15(2), 255; https://doi.org/10.3390/ph15020255 - 20 Feb 2022

Cited by 16 | Viewed by 2982

Abstract

Gender medicine in the field of oncology is an under-researched area, despite the existing evidence towards gender-dependent response to therapy and treatment-induced adverse effects. Oncological treatment aims to fulfil its main goal of achieving high tumour control by also protecting normal tissue from acute or chronic damage. Chemotherapy is an important component of cancer treatment, with a large number of drugs being currently in clinical use. Cisplatin is one of the most commonly employed chemotherapeutic agents, used either as a sole drug or in combination with other agents. Cisplatin-induced toxicities are well documented, and they include nephrotoxicity, neurotoxicity, gastrointestinal toxicity, ototoxicity, just to name the most frequent ones. Some of these toxicities have short-term sequelae, while others are irreversible. Furthermore, research showed that there is a strong gender-dependent aspect of side effects caused by the administration of cisplatin. While evidence towards sex differences in animal models is substantial, clinical studies considering sex/gender as a variable factor are limited. This work summarises the current knowledge on sex/gender-related side effects induced by platinum compounds and highlights the gaps in research that require more attention to open new therapeutic possibilities and preventative measures to alleviate normal tissue toxicity and increase patients’ quality of life in both males and females. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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14 pages, 481 KiB

Open AccessReview

Just a Reflection: Does Drug Repurposing Perpetuate Sex-Gender Bias in the Safety Profile?

by Ilaria Campesi, Giorgio Racagni and Flavia Franconi

Pharmaceuticals 2021, 14(8), 730; https://doi.org/10.3390/ph14080730 - 27 Jul 2021

Cited by 8 | Viewed by 3211

Abstract

Vaccines constitute a strategy to reduce the burden of COVID-19, but the treatment of COVID-19 is still a challenge. The lack of approved drugs for severe COVID-19 makes repurposing or repositioning of approved drugs a relevant approach because it occurs at lower costs and in a shorter time. Most preclinical and clinical tests, including safety and pharmacokinetic profiles, were already performed. However, infective and inflammatory diseases such as COVID-19 are linked with hypoalbuminemia and downregulation of both phase I and phase II drug-metabolizing enzymes and transporters, which can occur in modifications of pharmacokinetics and consequentially of safety profiles. This appears to occur in a sex- and gender-specific way because of the sex and gender differences present in the immune system and inflammation, which, in turn, reflect on pharmacokinetic parameters. Therefore, to make better decisions about drug dosage regimens and to increases the safety profile in patients suffering from infective and inflammatory diseases such as COVID-19, it is urgently needed to study repurposing or repositioning drugs in men and in women paying attention to pharmacokinetics, especially for those drugs that are previously scarcely evaluated in women. Full article

(This article belongs to the Special Issue Adverse Drug Reactions and Gender Differences)

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